RAGE Signalling in Acute Inflammatory Disorders: Therapeutic Potential of Natural Products

Acute inflammatory disorders, including acute lung injury, acute pancreatitis, ischaemia–reperfusion injury, and sepsis, are major clinical challenges characterised by rapid progression, a characteristic cytokine storm, and high mortality rates. The receptor for advanced glycation end-products (RAGE) serves as a pivotal multi-ligand pattern recognition receptor that integrates PAMPs and DAMPs. Excessive RAGE engagement triggers detrimental signalling cascades, notably NF-κB and MAPKs, which exacerbate hyperinflammation and lead to progressive organ dysfunction. Consequently, the RAGE axis represents a potent therapeutic target for mitigating hyperinflammation and improving clinical outcomes in acute inflammatory disorders. While initial pharmacological efforts focused on synthetic inhibitors and biologics, there is a shifting focus toward bioactive alternatives with high safety profiles. Here, we present recent molecular insights into RAGE-mediated pathogenesis in acute inflammatory disorders and evaluate current therapeutic strategies. Furthermore, we emphatically summarise the bioactive natural products, including terpenoids, flavonoids, alkaloids, and a xanthone, that prevent and treat acute inflammatory disorders by disrupting RAGE–ligand interactions and suppressing downstream oxidative stress and cytokine release. Integrating these molecular mechanisms with the pharmacological profiling of natural RAGE modulators provides a robust foundation for the development of next-generation therapeutic strategies to improve clinical outcomes in acute inflammatory disorders.